BACKGROUND: Osteoarthritis (OA) is a chronic progressive illness for which effective therapy is needed. We hypothesize that periarticular factors such as body fatness and muscle function are important determinants of mobility function, and also the development of knee OA, and that muscle function is compromised by local but not systemic inflammation. EPIDEMIOLOGIC STUDIES OF OSTEOARTHRITIS AND AGING We are conducting a study to delineate the relationship between muscle, bone and fat and knee OA, and explore the possible role of various inflammatory, metabolic and hormonal factors as mediators of these relationship using stored serum specimens obtained from BLSA participants up to 10 years prior to their developing radiographic knee OA. Testing of blood and urine biomarkers of cartilage and bone metabolism are in progress. We are also integrating clinically relevant measures of joint, bone and muscle function to assess musculoskeletal aging into the BLSA. By integrating state-of-the-art imaging and physiologic measures of muscle, bone, and joints we will be better able to delineate healthy aging, the transition into common age-associated diseases (i.e. osteoarthritis, osteoporosis), and study the complex interplay between the processes that profoundly influence mobility function in late life. We analyzed data acquired from participants of the Women?s Health and Aging Studies in close collaboration with the Johns Hopkins University?s Center for Aging and Health to delineate the relationship between knee OA and functional limitations. We examined the relationship between knee OA and mobility function in the WHAS II cohort comprised of 436 high functioning older women. Despite their high level of self-reported function, performance was slower and task modification more frequently reported amongst the 117 women with KOA than the 285 women without KOA. These findings imply that mobility function impairment occurs early in knee OA. Furthermore, lower knee extensor strength, higher body weight, and greater pain severity were associated with OA, and also with functional limitations. These results have been published. CLINICAL STUDY OF KNEE OSTEOARTHRITIS We initiated a clinical study to determine whether muscle strength, mass and function important determinants of mobility function in adults with knee OA, and explore the extent to which these characteristics are associated with local inflammatory factors and circulating biomarkers. We are recruiting adults 50 years and older with and without osteoarthritis of the knee of comparable age, body weight and physical activity level. Although preliminary, we are observing interesting trends in motor-unit physiology that may be associated with the disease. Enrollment is ongoing. In collaboration with members of the Johns Hopkins Arthritis Center, we have initiated a study to determine whether the inflammatory markers associated with knee OA change as weight reduction achieved by lifestyle physical activity modification and tailored exercise program. Lifestyle modification results in accumulated physical activity and exertion throughout the day and over the course of weeks. Tailored exercise incorporates exercises that are feasible for each individual. We will examine relationships between cartilage and bone biomarkers, knee pain and change in weight. The recruitment and enrollment are underway. Sample testing has commenced. RESEARCH USING ANIMAL MODELS OF ARTHRITIS AND PHYSICAL INACTIVITY We have embarked on rodent studies in close collaboration with the NMR unit of the Laboratory of Clinical Investigation to 1) delineate the functional and morphologic characteristics of skeletal muscle that are associated with arthritis, 2) determine whether arthritis-associated skeletal muscle properties is distinct from that induced by physical inactivity, and 3) explore the associations between muscle function, local and circulating inflammatory mediators. We conducted 2 parallel experiments using rodent models of arthritis. Female 3-4 month old F344 rats were induced to develop arthritis by collagen injection or intra-articular papain injection and compared to a hind-limb unloaded model of physical inactivity. Animals underwent NMR spectroscopy. Upon completion of NMR experimentation, bone samples were subjected to micro-CT examination. Blood and muscle samples acquired upon completion of the NMR procedure were tested for interleukins (IL)-1, -6, tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma by ELISA and multiplex assays. Although right and left muscle cytokine levels were well correlated (r >0.80; p < 0.05), serum levels did not predict muscle levels of the above cytokines (6). Mean interleukin-1 concentration was higher in Papain and CIA rat muscle samples than controls. IFN-gamma level was significantly lower in the CIA (25.80 mcg/ml) and higher in HU animals (81.62 mcg/ml) than CTLs (99.1 mcg/ml), and lowest in the CH group (17.49 mcg/ml) (7). Mean IL-6 level was significantly lower in the combined CH group (16.96 mcg/ml) than CTLs (68.78 mcg/ml). The groups did not differ significantly with regard to serum cytokine levels. We conclude from this experiment that arthritis and atrophy result in bioenergetically, and immunologically distinct muscle characteristics. Furthermore, early arthritis and physical inactivity appear to exert measurable effects on bone quality that are demonstrable by micro-CT. SUMMARY We are striving to develop a coordinated approach that spans epidemiologic, clinical and basic science that will contribute to our understanding of the mechanisms of skeletal muscle malfunction in the context of arthritis, and the interactions between muscle, bone and circulating and locally-produced mediators of inflammation, and also constitutes a foundation upon which new therapeutic interventions strategies can be developed.